Imagine it’s a hot summer day and your air conditioning stops working. Seeking relief, you quickly buy your favourite freshly squeezed grapefruit juice from the store. Although initially refreshed, you soon feel nauseous with an elevated heart rate. You later find out that grapefruit juice contains furanocoumarins, compounds that interfere with the metabolism of your medication, causing these adverse effects.
The typical pathway of an oral drug acting in the body begins with absorption, where the ingested drug travels to the stomach and small intestine (Caldwell, Gardner, and Swales 1995). Before the drug can take effect, it must dissolve and enter the bloodstream, where it is distributed to target tissues. Once the drug has performed its therapeutic effects, it is ready to be metabolized. At this point, the drug is converted into a water-soluble form and is essentially inactivated, allowing the drug to be excreted through natural body processes. However, it is at this metabolization step that the furanocoumarins in grapefruit juice produce harm. Furanocoumarins interfere with the role of a family of enzymes in the liver known as Cytochrome P450 (CYP3A4), a primary catalyst for oxidizing most drugs and breaking them down into metabolites (Ho, Saville, and Wanwimolruk 2001). When these furanocoumarins are consumed, they are metabolized by the CYP3A4 and converted into intermediates that have the ability to covalently bond to the enzyme’s active site (Bailey, Dresser, and Arnold 2013). The covalent bond irreversibly inactivates CYP3A4 in the small intestine, prohibiting the deactivation of the drug. Once these compounds bind, CYP3A4 is deactivated for several days and can no longer metabolize another drug in the body until new enzymes are synthesized. When approximately 200 mL of grapefruit juice is mixed with specific drugs, the drug is not metabolized effectively, and a buildup of the substance causes increased rates of toxicity in the bloodstream (Bailey, Dresser, and Arnold 2013).
Grapefruit’s impact on medications is drug-specific, rather than applying to entire classes of drugs (Jargin 2017). These drugs typically exhibit three main features in common with each other: they are only administered orally, they have a low to moderate inherent oral bioavailability, and they depend on CYP3A4 for their metabolism (Bailey, Dresser, and Arnold 2013). For example, felodipine is a calcium channel blocker that is prescribed to help manage hypertension but is susceptible to the effects of furanocoumarins (Guo and Yamazoe 2004). Under normal conditions, this drug goes through first-pass metabolism by CYP3A4 in both the liver and small intestine. However, when grapefruit juice is introduced to the system, the irreversible inhibition of CYP3A4 occurs specifically in the intestinal tract, and the lack of metabolization causes felodipine to be left in the bloodstream (Figure 1). This can increase severity of the typical adverse effects of felodipine, such as dizziness, fainting, reflex tachycardia, and headaches.
Figure 1: First-pass metabolism of CYP3A4 substrate (ie. felodipine) without furanocoumarins in (a) the intestinal tract and (b) the liver. The substrate is seen to be partially metabolized before reaching systemic circulation. The presence of furanocoumarins in (c) the intestinal tract and (d) the liver is also depicted. The products that contain furanocoumarins inhibit the intestinal CYP3A4 metabolism, resulting in a reduced drug breakdown and higher concentrations of the unmetabolized drug that is entering the substrate (Seden et al. 2010).
Although doses of furanocoumarins are not harmful to the average person, their interaction with certain medications can be quite dangerous and cause serious complications. As scientific research progresses, scientists have begun to explore the idea of furanocoumarins-free citrus juices, which retains the flavour of the juice, but still minimizes the risk of drug interactions (Paine et al. 2006). Until then, the next time you reach for that refreshing glass of grapefruit juice, it may be worth considering what is inside your medicine cabinet first.
References
Bailey, David G., George Dresser, and J. Malcolm O. Arnold. 2013. “Grapefruit–Medication Interactions: Forbidden Fruit or Avoidable Consequences?” CMAJ 185 (4): 309–16. https://doi.org/10.1503/cmaj.120951.
Caldwell, John, Iain Gardner, and Nicola Swales. 1995. “An Introduction to Drug Disposition: The Basic Principles of Absorption, Distribution, Metabolism, and Excretion.” Toxicologic Pathology 23 (2): 102–14. https://doi.org/10.1177/019262339502300202.
Ho, P. C., D. J. Saville, and S. Wanwimolruk. 2001. “Inhibition of Human CYP3A4 Activity by Grapefruit Flavonoids, Furanocoumarins and Related Compounds.” Journal of Pharmacy & Pharmaceutical Sciences 4 (3): 217–27.
Jargin, Sergei V. 2017. “Grapefruit: Some Perspectives in Pharmacology and Nutrition.” Journal of Intercultural Ethnopharmacology 6 (3): 339–41. https://doi.org/10.5455/jice.20170511061624.
Kiani, Jawad, and Sardar Z Imam. 2007. “Medicinal Importance of Grapefruit Juice and Its Interaction with Various Drugs.” Nutrition Journal 6: 33. https://doi.org/10.1186/1475-2891-6-33.
Paine, Mary F, Wilbur W Widmer, Heather L Hart, Susan N Pusek, Kimberly L Beavers, Anne B Criss, Sherri S Brown, Brian F Thomas, and Paul B Watkins. 2006. “A Furanocoumarin-Free Grapefruit Juice Establishes Furanocoumarins as the Mediators of the Grapefruit Juice–Felodipine Interaction2.” The American Journal of Clinical Nutrition 83 (5): 1097–1105. https://doi.org/10.1093/ajcn/83.5.1097.
Seden, Kay, Laura Dickinson, Saye Khoo, and David Back. 2010. “Grapefruit-Drug Interactions.” Drugs 70 (18): 2373–2407. https://doi.org/10.2165/11585250-000000000-00000.
Comments
13 Responses to “The Bitter Side of Grapefruit and Medication”
Hey isci,
I decided to write my blog post further exploring what the 2a18 cohort discussed in our drug discovery class. I stumbled upon a research paper discussing the effects of certain citruses on drug metabolization and I became very interested how the body responds to this. The integration of biological and chemistry-related concepts allowed me to fully understand this phenomenon and write a post about it. If you have any feedback, please leave a comment below!
Arjun
Hi Arjun,
This was a really interesting blog post, and I learned a lot! With that in mind, I had a few suggestions:
– If space permits, you could add an angle of evolutionary biology by discussing how grapefruit has adapted to have these compounds in the first place. I believe furanocoumarins are actually a defense mechanism in plants that evolved to deter herbivores and pathogens, but I would double check. It could just be an interesting thing to add to get more interdisciplinary science in this post.
– You could also discuss how genetics play a role in how people are affected by grapefruit juice if space permits. Specifically, individuals with genetically lower levels of CYP3A4 activity (due to polymorphisms in CYP3A4 genes) are already predisposed to slower drug metabolism, which means grapefruit juice doesn’t affect them as dramatically.
– Minor edit, but I would change “The covalent bond causes an irreversible inactivation process of CYP3A4 in the small intestine, prohibiting the deactivation of the drug” to “The covalent bond irreversibly inactivates CYP3A4 in the small intestine, prohibiting the deactivation of the drug” just to improve flow a bit.
Overall, great blog post! I think this topic is very interesting, and am excited to read the final copy.
Happy editing,
Siya
Hey Siya,
Thanks for your suggestions. Unfortunately, I am over the word count so I am working on a way to cut down the content. However, I will look into your first two suggestions just for my general knowledge! I went ahead and fixed my “The covalent bond causes an irreversible inactivation process of CYP3A4 in the small intestine, prohibiting the deactivation of the drug” sentence and changed it to what you suggested.
Thank you!
Hey Arjun,
Your post is very well written and caught my attention as soon as I read the title! I’ll definitely think twice before reaching for my next glass of grapefruit juice! Here are some quick edits to consider:
– For P1S5, the word “process” in “metabolization process” might be a bit redundant, and I would consider omitting it for conciseness.
– For P1S2, “favorite” should be “favourite” 🙂
– If this was accessed online your third citation for Ho, P. C., D. J. Saville, and S. Wanwimolruk (2001) may require a DOI or URL in, something you might want to double-check!
– I’d suggest improving the readability of S4 in your figure caption, by changing “The furanocoumarins containing products inhibit” to “The products containing furanocoumarins inhibit” which would make it more clear!
But overall, this was a well-rounded and insightful post. Happy editing !
Ann
Hey Ann,
Thanks for the comment! I appreciate you taking time to read my post. I fixed the suggestions for p1s2, so thank you. Unfortunately the Ho, P. C., D. J. Saville, and S. Wanwimolruk (2001) source doesn’t have a DOI but since it is still from a reliable source, it is acceptable to use. I also changed it to “The products containing furanocoumarins inhibit” in S4 of my figure caption. I also decided to leave in “metabolization process” in the first paragraph
Thank you!
Hi Arjun,
I really enjoyed reading your blog post! The way you connected a common scenario (grapefruit juice on a hot day) to a complex scientific concept made it relatable. Here are some suggestions that you may consider to incorporate in your final copy:
– In the first paragraph, consider changing the hyphen to an em dash.
– The phrase “bringing forth these adverse effects” could be reworded for better flow, such as “leading to these adverse effects.”
– Consider rephrasing “the covalent bond causes an irreversible inactivation process of CYP3A4 in the small intestine, prohibiting the deactivation of the drug” for clarity, such as “prohibiting the metabolism of the drug” instead of “deactivation.”
– While the explanation of CYP3A4 inhibition is thorough, you could include a brief list of common medications that interact with grapefruit (e.g., statins, certain blood pressure medications) for reference.
– In the final paragraph, “furanocoumarins-free” might read more smoothly as “furanocoumarin-free”.
I can’t wait to see your final product. Happy editing!
Alesia
Hey Alesia,
Thanks for the comment! I implemented your first three suggestions, so thank you for that. As for your fourth suggestion, I would love to include common medications that interact with grapefruit, but I am unfortunately out of space (and actively trying to condense the word count).
Thank you!
Hey Arjun, your blog post about grapefruit and its implications on the human body is super cool! Your piece is informative, engaging and well-structured. Here are some recommendations for your final!
1) The opening story is really nice, but it could be a bit more concise whilst still being engaging. Maybe consider including a scientific issue or fact to help substantiate it. Like this, “Seeking relief, you head to a juice bar for a refreshing glass of freshly squeezed grapefruit juice.”
2) The flow across many of your sentences is amazing, but here are a few that need work:
a) Instead of “”The drug goes through a dissolution process, so that the active drug molecules can diffuse into the bloodstream and begin being distributed to their target tissues.” you can say “Before the drug can take effect, it must dissolve and enter the bloodstream, where it is distributed to target tissues.”
b) The covalent bond causes an irreversible inactivation process of CYP3A4 in the small intestine, prohibiting the deactivation of the drug.”. Instead, use a bit of a more simpler and easier to understand sentence like “Once furanocoumarins bind to CYP3A4, they permanently disable the enzyme, preventing it from breaking down certain drugs. As a result, drug levels in the bloodstream rise, increasing the risk of toxicity.”
Other than that, the blog is great! Looking forward to reading your final.
Hey Vibi,
Thanks for the comment. I implemented your first suggestion by condensing the first paragraph. I also fixed my writing to implement the suggestions you made for the second and third one.
Thank you!
Hi Arjun
I really enjoyed reading your blogpost, below are some suggestion I hope you’ll find helpful:
– Consider condensing down your introduction currently a majority of it serves as the hook but it may be wise to shorten the hook section and introduce the main ideas you will be discussing on furanocoumarins.
– in your introduction you mention “a compound known as furanocoumarins” furanocoumarins is a actually class of organic compounds rather than a singular one so I would suggest changing your introduction to reflect this
– in your second paragraph second sentence, clarify that the dissolution process occurs next in the stomach and small intestine
– In your third sentence of second paragraph, consider rewording “once the drug has performed its therapeutic effects” as the drug being metabolized doesn’t always mean therapeutic effects have been reached first
Overall this was a very well written blogpost and I look forward to reading the final draft!
Ethan
Hello Ethan,
Thanks for taking time to read my post. I condensed the beginning of the post and adjusted the wording as per your first and second suggestion, so thank you! I also clarified that the dissolution process occurs next in the stomach and small intestine in the second paragraph. Thank you!
Arjun
Hi Arjun,
Loved reading your blog post, here are some suggestions for next time!
-Consider putting your figure in the centre
-Perhaps rewrite some of the information in paragraph 2 around ” furanocoumarins in grapefruit juice” in the paragraph below to be more concise and add more flow
– Consider changing all hyphens to an em dash, I believe there was one in your first paragraph
-link your sources as per ISCI document format
-Italicize your figure caption
Overall great work! Excited to read the final product!!
Lola
Hey Lola,
Thanks for the comment. I italicized and centred my figure, thanks for the reminder. I also rewrote some of the information in p2 as per your suggestion. I also changed it to an EM dash and not a hyphen.
Thank you!
Arjun